Aldosterone-Regulating Receptors and Aldosterone-Driver Somatic Mutations.

Background: Somatic gene mutations that facilitate inappropriate intracellular calcium entrance have been identified in most aldosterone-producing adenomas (APAs). Studies suggest that angiotensin II and adrenocorticotropic hormone (ACTH) augment aldosterone production from APAs. Little is known, however, regarding possible variations in response to hormonal stimuli between APAs with different aldosterone-driver mutations.

Objective: To analyze the transcript expression of type 1 angiotensin II receptors (), ACTH receptors (), and melanocortin 2 receptor accessory protein () in APAs with known aldosterone-driver somatic mutations.

Methods: RNA was isolated from APAs with mutations in: (n = 14), (n = 14), (n = 14), and (n = 5), and from normal adjacent adrenal tissue (n = 45). Transcript expression of , , , aldosterone synthase (), 17α-hydroxylase/17,20-lyase (), and 11β-hydroxylase () were quantified using quantitative RT-PCR and normalized to β-actin.

Results: Compared to adjacent normal adrenal tissue, APAs had higher transcript levels of (2,216.4 [1,112.0, 2,813.5]-fold, < 0.001), (2.88 [2.00, 4.52]-fold,  < 0.001), and (1.80 [1.02, 2.80]-fold, < 0.001]), and lower transcript levels of , , and (0.28-0.36, < 0.001 for all). and transcripts were lower in APAs with other mutations ( < 0.01 for both). expression correlated positively with that of in APAs harboring and mutations, and with expression in APAs harboring ase mutations.

Conclusions: While and are expressed in all APAs, differences were observed based on the underlying aldosterone-driver somatic mutations. In tandem, our findings suggest that APAs with -mutations are more responsive to ACTH than -mutated APAs.